DESCRIPTION (Investigator's Abstract): During learning and development, the number and strength of synaptic inputs received by a neuron may change dramatically. Such changes are crucial for sculpting functional circuits and generating behavioral flexibility, but they raise a compelling problem for the nervous system: that is how do neurons and circuits maintain stability in their firing properties in the face of such dramatic synaptic configuration? In particular, how do neurons maintain their firing rate in the correct dynamic range despite large fluctuations in the total amount of synaptic excitation they receive? One possibility is that neuronal activity levels can regulate synaptic strengths to maintain firing rates within certain boundaries. In preliminary experiments we have tested this hypothesis. We found that activity can bidirectionally modify the amplitude of miniature excitatory synaptic currents (mEPSCs) between cultured cortical pyramidal neurons. These modifications act to maintain stability in firing rates; increased activity decreases excitatory synaptic strength, and vice versa. In addition, inhibition in these cultures in regulated by activity in the opposite direction from excitation. This activity dependent regulation of synaptic strengths could serve to maintain relatively constant firing rates over broad changes in the number and strength of synaptic inputs. In addition, because this regulation acts to oppose traditional long-term potentiation, it can prevent saturation of synaptic strength arising from the correlation-based synaptic modifications thought to underlie some forms of leaning and memory. The proposal has five specific aims: 1) Hemostatic regulation of firing rates and mEPSC amplitude in cortical pyramidal; 2) Do excitatory synaptic strength vary as a function of firing rate or receptor activation?;3) Homeostasis of inhibitory synaptic connections between cortical interneuron and pyramidal neurons; 4) Role of neurotrophins and calcium influx in synaptic homeostasis; and 5)synaptic homeostasis in vivo.